Tissue-Resident Bone Marrow–Derived Progenitor Cells Key Players in Hypoxia-Induced Angiogenesis

University of Rochester, Rochester, New York, United States
Circulation Research (Impact Factor: 11.02). 12/2005; 97(10):955-7. DOI: 10.1161/01.RES.0000193566.65262.d8
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    • "Another possibility is that cell-to-cell interaction between endothelial cells and other types of cells is important in enhancing multiple angiogenic pathways [20]. Bone marrow-derived progenitor cells and residential stem cells have been shown to contribute to angiogenesis process [21]. Xu et al. reported that LIPUS stimulated hematopoietic stem/progenitor cell viability, proliferation and differentiation in vitro [22]. "
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    ABSTRACT: Background Although a significant progress has been made in the management of ischemic heart disease (IHD), the number of severe IHD patients is increasing. Thus, it is crucial to develop new, non-invasive therapeutic strategies. In the present study, we aimed to develop low-intensity pulsed ultrasound (LIPUS) therapy for the treatment of IHD. Methods and Results We first confirmed that in cultured human endothelial cells, LIPUS significantly up-regulated mRNA expression of vascular endothelial growth factor (VEGF) with a peak at 32-cycle (P<0.05). Then, we examined the in vivo effects of LIPUS in a porcine model of chronic myocardial ischemia with reduced left ventricular ejection fraction (LVEF) (n = 28). The heart was treated with either sham (n = 14) or LIPUS (32-cycle with 193 mW/cm2 for 20 min, n = 14) at 3 different short axis levels. Four weeks after the treatment, LVEF was significantly improved in the LIPUS group (46±4 to 57±5%, P<0.05) without any adverse effects, whereas it remained unchanged in the sham group (46±5 to 47±6%, P = 0.33). Capillary density in the ischemic region was significantly increased in the LIPUS group compared with the control group (1084±175 vs. 858±151/mm2, P<0.05). Regional myocardial blood flow was also significantly improved in the LIPUS group (0.78±0.2 to 1.39±0.4 ml/min/g, P<0.05), but not in the control group (0.84±0.3 to 0.97±0.4 ml/min/g). Western blot analysis showed that VEGF, eNOS and bFGF were all significantly up-regulated only in the LIPUS group. Conclusions These results suggest that the LIPUS therapy is promising as a new, non-invasive therapy for IHD.
    Full-text · Article · Aug 2014 · PLoS ONE
    • "Tissue hypoxia is frequently found under various pathophysiological conditions, such as circulatory failure, myocardial infarction and cerebral ischemia (Garin et al., 2005; Li and Jackson, 2002; McCord, 1985; Michiels, 2004). Owing to the high incidence and clinical relevance of tissue hypoxia and ischemia-reperfusion injury, an understanding of the hypoxia-associated cellular and molecular mechanisms is essential for the development of new and effective strategies to reduce ischemia-reperfusion-and tissue-hypoxiamediated cell damage. "
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    ABSTRACT: Ischemia/reperfusion injury and tissue hypoxia are of high clinical relevance, as they are associated with various pathophysiological conditions such as myocardial infarction and stroke. Nevertheless, the underlying mechanisms of the ischemia/reperfusion induced cell damage are still not fully understood, which is at least partially due to the lack of cell culture systems for the induction of rapid and transient hypoxic conditions. Aim of the study was to establish a model that is suitable for the investigation of cellular and molecular effects associated with transient and long-term hypoxia and to gain insights into hypoxia mediated mechanisms employing a neuronal culture system. A semipermeable membrane insert system in combination with the hypoxia inducing enzymes glucose oxidase and catalase was employed to rapidly and reversibly generate hypoxic conditions (pO2<10mmHg) in the culture medium. Hydrogen peroxide assays, glucose measurements and westernblotting were performed to validate the system and to evaluate the effects of the generated hypoxia on neuronal IMR-32 cells. Using the insert based two-enzyme model, hypoxic conditions were rapidly induced in the culture medium (pO2 0 minutes: 107.57±0.99mmHg, 70 minutes: 9.00±0.58mmHg, 120 minutes: 5.00±0.00mmHg, 170 minutes: 2.00±0.00mmHg, 360 minutes: 2.00±0.00mmHg). Glucose concentrations gradually decreased ([Glc] 0 minutes: 4.50±0.02g/l, 360 minutes: 1.22±0.07g/l) while levels of hydrogen peroxide were not altered ([H2O2] 0 minutes: 9.57±0.00µM, 360 minutes: 7.96±0.67µM). Moreover, a rapid and reversible (on/off) generation of hypoxia could be performed by the addition and subsequent removal of the enzyme containing inserts. Employing neuronal IMR-32 cells, we showed that 3 hours of hypoxia led to morphological signs of cellular damage and significantly increased levels of LDH as a biochemical marker of cell damage (hypoxia: 0.50±0.08a.u., normoxia: 0.20±0.05a.u.; P<0.05). Hypoxic conditions also increased the amounts of cellular procaspase-3 (hypoxia: 1.45±0.19a.u., normoxia: 0.98±0.01a.u.; P<0.05) and catalase (hypoxia: 1.71±0.55a.u., normoxia: 0.61±0.09a.u.; P<0.05) as well as phosphorylation of the prosurvival kinase Akt (hypoxia: 0.65±0.14a.u., normoxia: 0.05±0.01a.u.; P<0.05), but not Erk1/2 or STAT5. In summary, we present a novel framework in investigating hypoxia mediated mechanisms on cellular level. We claim that the model, the first of its kind, enables researches to rapidly and reversibly induce hypoxic conditions in-vitro without interference of the hypoxia inducing agent with the cultured cells. The system may help to further unravel hypoxia associated mechanisms which are clinically relevant in various tissues and organs.
    No preview · Article · Sep 2013 · Disease Models and Mechanisms
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    ABSTRACT: A hypothesis about the inflammatory etiopathogeny mediated by astroglia of hepatic encephalopathy is being proposed. Three evolutive phases are considered in chronic hepatic encephalopathy: an immediate or nervous phase with ischemia-reperfusion, which is associated with reperfusion injury, edema and oxidative stress; an intermediate or immune phase with microglia hyperactivity, which produces cytotoxic cytokines and chemokines and is involved in enzyme hyperproduction and phagocytosis; and a late or endocrine phase, in which neuroglial remodeling, with an alteration of angiogenesis and neurogenesis, stands out. The increasingly complex trophic meaning that the metabolic alterations have in the successive phases making up this chronic inflammation could explain the metabolic regression produced in acute and acute-on-chronic hepatic encephalopathy. In these two types of hepatic encephalopathy, characterized by edema, neuronal nutrition by diffusion would guarantee an appropriate support of substrates, in accordance with the reduced metabolic needs of the cerebral tissue.
    No preview · Article · Jan 2007 · European Journal of Gastroenterology & Hepatology
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